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TitleParkinson's disease kinase LRRK2 coordinates a cell-intrinsic itaconate-dependent defence pathway against intracellular Salmonella.
Journal, issue, pagesNat Microbiol, Vol. 8, Issue 10, Page 1880-1895, Year 2023
Publish dateAug 28, 2023
AuthorsHuan Lian / Donghyun Park / Meixin Chen / Florian Schueder / Maria Lara-Tejero / Jun Liu / Jorge E Galán /
PubMed AbstractCell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen ...Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen Salmonella, through delivery of antimicrobial itaconate. Here we show that the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) orchestrates this defence response by scaffolding a complex between RAB32 and aconitate decarboxylase 1, which synthesizes itaconate from mitochondrial precursors. Itaconate delivery to Salmonella-containing vacuoles was impaired and Salmonella replication increased in LRRK2-deficient cells. Loss of LRRK2 also restored virulence of a Salmonella mutant defective in neutralizing this RAB32-dependent host defence pathway in mice. Cryo-electron tomography revealed tether formation between Salmonella-containing vacuoles and host mitochondria upon Salmonella infection, which was significantly impaired in LRRK2-deficient cells. This positions LRRK2 centrally within a host defence mechanism, which may have favoured selection of a common familial Parkinson's disease mutant allele in the human population.
External linksNat Microbiol / PubMed:37640963 / PubMed Central
MethodsEM (subtomogram averaging)
Resolution19.0 - 25.0 Å
Structure data

EMDB-41046: Subtomogram average structure of the injectisome
Method: EM (subtomogram averaging) / Resolution: 25.0 Å

EMDB-41047: Intermembrane Tether between SCV and Mitochondria
Method: EM (subtomogram averaging) / Resolution: 19.0 Å

Source
  • Salmonella enterica (bacteria)

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